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Management of head and neck hemangiomas in China

ZHENG, Jia-wei; ZHOU, Guo-yu; WANG, Yan-an; ZHANG, Zhi-yuan

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Hemangioma is a common benign vascular tumor, with an incidence of 2%-3% in the neonate and 10% in baby after 1 year.1 The incidence of hemangiomas is approximately 22%-30% of preterm infants with birthweight less than 1000 g. The development of hemangioma is therefore supposed to be related to various intra- and extra-uterine factors.

Females are affected more often than males by a ratio of 3:1-5:1.1 Hemangioma can be found in all regions of the body, but 60% are localized on the head and neck, 25% on the trunk, and 15% on the extremities. Most of the lesions are focal and solitary, while 15%—20% are multiple with involvement of extracutaneous sites; including the liver, gastrointestinal tract, larynx, central nervous system, pancreas, gall bladder, thymus, spleen, lymph nodes, lung, urinary bladder, and adrenal glands.

Although infantile hemangioma is usually benign, its growth is very unpredictable due to uncontrollable endothelial cell proliferation. Infantile hemangioma has a varied appearance depending on the location of the lesion, the depth of the hemangioma and the size. In the early phase white or pink spots are often noted. Sometimes, it appears as port wine stain-like lesion or fine telangiectasias surrounded by a faint halo of vascular blanching. The lesion grows rapidly and unproportionally during the first several weeks (usually 4 weeks) after birth into the proliferative phase, which usually lasts for 6 months.2,3 Capillary hemangioma and carvenous hemangioma were usually used to describe various types of hemangiomas in the past, but these terms are not exact, for many so-called carvenous hemangiomas are actually vascular malformations rather than true hemangiomas. Therefore, an important concept is that hemangioma is a true vessel cell tumor with distinct clinical and biological characteristics derived from vascular malformations. It can be divided into cutaneous, subcutaneous or mixed type depending on the depth of the lesions. The colour of the hemangioma is varied, mostly depended on the extent and depth of the lesion, the diameter of the involved vessels, the primary site, the skin temperature, as well as the status of the infancy such as crying or exciting.

CLINICAL CHARACTERISTICS

Hemangioma features a rapid proliferative phase followed by an involutive phase. At the end of 1 year the lesion begins to regress and arrests in growth. The colour changes from pink red to deep red. Involution usually lasts longer than proliferation and may persist for 1 to 10 years. In the involution phase, endothelial cells decrease in number and are substituted by fatty and fibrous tissues. Although most hemangiomas can resolve spontaneously, approximately 50%-60% of all hemangiomas resolve incompletely, leaving permanent changes in the skin. These changes include telangiectases, superficial dilated veins, stippled scarring, anetoderma or epidermal atrophy (particularly with superficial lesions), hypopigmentation and/or redundant skin with fibro-fatty residua (especially with subcutaneous lesions). Patients with ulcerations easily develop scars after healing. The residual lesions are related to the size and location of the primary hemangiomas, and usually need to be surgically corrected.

The clinical and biological characteristics of hemangioma have a small but significant percentages of hemangiomas of infancy that develop complications; such as ulcer, secondary infection, bleeding, facial deformities and eye problems. Hemangiomas arising in the submandibular area are easily accompanied by respiratory problems; such as laryngeal stridor, hoarseness or even dyspnea. Laryngopharyngeal bronchoscopy is recommended for early detection and management in this circumstance.

The diagnosis of hemangioma is normally made based on the history and clinical findings. In some cases, especially those with deep lesions, difficulties may exist in differentiating hemangiomas from vascular malformations. Patients can be observed for several days or weeks to see any changes of the lesions. If diagnosis is still uncertain, color Doppler ultrasonography and/or MRI may be used to aid in the diagnosis. Color Doppler ultrasonography is considered to be the most cost-effective imaging technique for the evaluation of hemangiomas. A proliferating hemangioma demonstrates nonspecific echogenicity with increased color flow and a high-flow pattern with an arterial and venous component. Numerous vessels are visualized (>5/cm2) with a high Doppler shift (>2 kHz) and low resistance. Using the criteria of high vessel density (>5/cm) and a high Doppler shift (>2 kHz), Dubois et al4 were able to achieve a sensitivity of 84% and a specificity of 98% in the diagnosis of hemangiomas. MRI is probably the single best modality to characterize vascular birthmarks. In MRI, proliferating hemangiomas demonstrate well defined, lobulated homogeneous soft-tissue masses. They are isotense-to-hypotense relative to muscle on T1 weighted images, and hypertense relative to muscle on T2 weighted images. Flow voids are seen within and around the lesions on spin echo images.

The management of hemangiomas remains a subject of considerable controversy both in China and world wide. One frequently raised question is the necessity to treat this benign lesion that can resolve spontaneously. Indeed, the majority of hemangiomas require no intervention and in general the ultimate cosmetic outcome is usually better in hemangiomas that are allowed to involute spontaneously than those treated too actively. One should keep in mind that hemangiomas can result in a variety of problems and impacts on children. The most serious situations are hemangiomas involving the upper aerodigestive tract and trachea. If laser therapy or tracheostomy is not applied adequately, the patients will have airway obstruction, asphyxia or even die.5 Hemangiomas in or around the eye requires early treatment to prevent amblyopia.6 Extensive cutaneous hemangiomas may lead to skin necrosis, ulceration and secondary infection,7 causing a series nursing care problems.

The second category of problems caused by hemangiomas are not life-threatening or function-impairing sequelae, but various psychological problems due to disfigurement, such as negative self-image evaluation, lack of self-confidence and distress, etc.

The third category of problem caused by hemangiomas is its unpredictability in growth several weeks or months after birth. There are now objective methods and variables to assess the extent of involution up to now. About 90% of infantile hemangiomas will involute eventually, but there are still 10% of them that will continue to grow with various complications. Therefore, it is imperative to control the growth of enlarging hemangiomas. Based on our clinical experiences on 165 cases and on literature reports, early and proper treatment of problematic hemangiomas is mandatory and effective.

Many treatment modalities are currently available for management of head and neck hemangiomas, including careful observation, drug therapy, laser and operative therapy. Controversies still exist as to when and how to treat based on these treatment tools. One should understand the natural history of hemangioma and the indications of each method prior to giving treatment to the individual patient. In our opinion, treatment of hemangiomas should be dependent on the location, extent, growing phase of the lesions and techniques available. There is no gold-standard treatment applicable to all patients. The principles of management of hemangiomas are accelerating the resolution of the lesions, minimizing the psychosocial distress caused by the lesions, and minimizing any morbidity related to the treatment of the lesions.8 We would add that an attempt should be made to use the available methods in a reasonable order to normalize the child's appearance before entering school.

“WAIT AND SEE”

“Wait and see” used to be the widely accepted policy for management of hemangiomas. During the first several weeks after birth, the lesion is too small to be treated or early intervention may lead to severe complications. In the proliferative phase, the parents were instructed to observe closely in the hope of spontaneous regression. Usually, the lesion continues to enlarge and the parents visit the physician again, but there is no satisfactory treatment to be used, and the lesion has caused considerable cosmetic or functional problems.

Nowadays, with the advent of various new techniques, especially the use of novel laser therapy, this old paradigm has been changed to benefit the patients. As it is impossible to precisely predict if the natural course of hemangioma is towards spontaneous resolution or continuous growth. If no intervention is delivered but only “wait and see”, most of the patients will not tolerate the long-term disfigurement. Therefore, early treatment in selected cases seems to be most important and imperative. The aim of intervention in this stage is to hinder enlargement of the lesion and accelerate regression. Facial hemangiomas are likely to develop ulceration and secondary infection, while hemangiomas arising from the upper aerodigestive tract may compress or obstruct the airway. Early treatment is therefore mandatory under these circumstances.

“Wait and see” is indicated in the following situations: (1) hemangiomas in non-vital sites, small in size, without rapid growing, have no significant impacts on appearance and function; (2) hemangiomas in involuting or involuted phase. During the follow-up period, the growth of the lesion should be monitored using objective means such as digital camera or B-mode ultrasonography. In addition, close observation is suggested to replace the so-called “wait and see”, and to be conducted by experienced physicians not untrained persons. Photographs should be taken at periodic intervals to help the parents see the regression of the lesion over time.

CRYOTHERAPY

CO2 rime and liquid nitrogen used to be applied in management of cutaneous hemangiomas, but is seldom utilized today due to limited indications (<10 mm in diameter, <2 mm in depth), unreliable efficacies and possible side effects such as skin scar and pigmentation.

LASER THERAPY

Laser therapy is indictable for treatment of early, superficial hemangiomas. In our opinion, the small red skin spot or macule discovered after birth should be removed with a laser, to arrest its subsequent rapid growth into the proliferative phase and alleviate further damages to the children as well as the psychological strain from the parents. For proliferating hemangiomas, laser therapy can accelerate regression, shrink the lesions, benefit the subsequent treatments and aid the children to achieve satisfactory appearance before school ages (5–6 years). Drug therapy (corticosteroids or Interferon) is considered if the lesions continue to enlarge during laser therapy.

There are several types of laser available for management of hemangiomas. Argon laser (514 nm in wavelength) can penetrate the skin to a depth of 0.5 mm, photocoagulate the hemoglobin within the vessels, and remove the superficial hemangiomas effectively. The shortest exposure time for response is 100 milliseconds. Histopathlogically, hemoglobin within the vessels of the irradiated lesions absorbs abundant energy after argon laser radiation, causing coagulation necrosis of the dermis and vascular embolization of the papillary layer without damage to the cutaneous appendages. Argon laser is quite effective for superficial telangiectasia and small, flat hemangioma, but the response of larger hemangiomas and deeper lesions is varied and limited.

Flashlamp-pumped pulsed dye laser (FPDL) (585 nm or 595 nm in wavelength) is the first laser specially designed to treat cutaneous vascular lesions and the first laser to eliminate these lesions predictably without producing a scar. It is characterized by a selective destruction of blood vessels by matching the wavelength of light absorbed by hemoglobin in the vessels and by using an exposure time less than the calculated thermal relaxation time (1–10 milliseconds) for the blood vessels. An exposure time of a millisecond or less was advocated to confine the heat to the vessel to decrease the risk of heat diffusion, which can cause skin scarring.

In contrast to argon laser, FPDL is the only laser that can cause thrombosis within the vessels without damage to the dermis. When adjusted to 585 nm, the depth of penetration for 50% of the energy is calculated to be 0.8 mm.9 Because the dermis of facial skin is approximately 0.6 mm deep in children and approximately 0.9 mm deep in adults, FPDL has proved to be a safe and effective treatment modality for superficial hemangiomas in the face. Clinically, FPDL is often applied with the following settings: a spot size of 5–10 mm, an energy density of between 5 to 7 J/cm2, with a maximum spot overlap of 20% to 30%.

The high pulse peak power of the FPDL disrupts the vessels. Immediately after radiation, the treated area turned blue-lilac (putpuric), with surrounding erythematous flare; this took 7 to 14 days to resolve. Some edema, especially in the periorbital area, was possible. If blanching or graying of the epidermis occurred during application, energy fluences were reduced to avoid blistering of the epidermis. After treatment, the treated areas were covered with panthenol ointment. In case of blistering or crusting, the patients' parents were instructed to cleanse the area with povidone-iodine solution. Furthermore, the parents were instructed to keep their children's fingernails short or have them wear gloves to avoid trauma to the treated areas. The patients were evaluated after 2 to 4 weeks, depending on the degree of response. The treatment might be repeated after the first session usually at a 4-week interval.

Hemangiomas with a deep or subcutaneous component do not benefit from FPDL treatment because the efficacy of the FPDL is limited by its depth of vascular injury.10 Furthermore, early intervention with FPDL may not prevent proliferative growth of the deeper or subcutaneous component of the hemangioma. Conversely, the deep component of the hemangioma continued to proliferate after FPDL treatment, whereas the superficial component resoled. In this case, we suggest administration of oral corticosteroids to arrest the growing of the lesions, or further therapy with Nd:YAG laser with continuous surface cooling with ice cubes.

Prior to FPDL treatment, superficial anesthesia is applied to the treated areas with topical anesthetic cream. During treatment, a cooling chamber can be used to protect the skin and relieve the pain. General anesthesia should be considered for children with extensive hemangiomas over a large dermatome and hemangiomas of periorbital area, especially if the eyelids were treated under the protection of the globe with an eye shield.

FPDL treatment is also beneficial to cutaneous hemangiomas during the involution phase. Some investigators may argue that superficial involuting hemangiomas need no treatment, in fact, many of these lesions are slow to resolve and can be present in a cosmetically or functionally prominent area, and patients can benefit from laser treatment with a quick response and simple operation before school ages.

Neodymium:yttrium aluminum garnet (Nd:YAG) laser is a kind of solid laser emitting a continuous wave infrared and invisible light with a wavelength of 1064 nm and a penetration depth of 1.0 mm. The laser energy can be absorbed mostly by blood while only a little is absorbed by surrounding tissues. Because of the longer wavelength, the Nd:YAG laser is capable of penetrating deeper into the tissue, with a depth of approximately 8.0 mm. To prevent thermal injuries to the adjacent tissues, ice cubes are used to cool the skin during irradiation.

In addition to direct irradiation, Nd:YAG laser is advantageous for interstitial application percutaneously through a Teflon catheter. To avoid carbonization of the tissue and catheter, the laser power is limited to be 5.0 to 8.0 watts, and the exposure time is less than 180 seconds. For hemangiomas arising from the upper aerodigestive tract, laser irradiation can be applied through an endoscopic catheter 600 μm in diameter in the following settings: an output power of 2 to 5 watts, an exposure time of 0.5 to 5.0 seconds.11 The laser beam can penetrate into and scatter within the deep tissues to be an ideal means for photocoagulation and hemostasis. It can be applied repeatedly with minimal edema and bleeding.

Nd:YAG laser with a percutaneous or intralesional application technique is a valuable tool for selected patients with larger or deeper (2.0 cm in depth) subcutaneous or mixed hemangiomas. The laser beam can be well focused on the lesion with a spot 2.0 mm in size. High output light can effectively photocoagulate and eliminate the lesion with adequate cooling to protect the adjacent tissues. The power of the laser is adjustable between 20 to 50 watts. For smaller deep red hemangiomas, lower power, 20 to 34 watts, is adopted with continuous cooling with ice cubes. For thicker subcutaneous hemangiomas, higher power, approximately 50 watts, is applied with continuous ice cooling. Subcutaneous hemangiomas may need repeated treatment at an interval of 4 to 6 weeks. These lesions often enlarge rapidly, and repeated laser treatment is helpful to slow progress and to accelerate resolution, even if it is unable to reduce the volume of the lesion. Hemangiomas located in the eyelids can also be effectively treated with Nd:YAG laser under strict protection of the eyes.

Nd:YAG laser treatment is very painful and should be performed under general anesthesia. Immediately after treatment the lesion becoms swollen and hardened. A blister or sometimes a scab may be present, but there is no necessity to incise the blister. Swelling often resolves 1 week after treatment, and the lesion becomes flat and blanched 2 to 4 weeks posttreatment.

The response rate of laser therapy for hemangiomas is between 77% and 100%. The size of hemangiomas at initial treatment is closely related to the final outcomes, the smaller the size, the better results. Most hemangiomas can be effectively treated and repeated treatment is demanded if the lesions continue to enlarge.

The effect of photocoagulation with the Nd:YAG laser is rapid, with minimal bleeding from the surrounding tissues and minor adverse reactions. However, intralesional Nd: YAG laser therapy with higher output power can result in atrophic skin scars in children. Permanent dyspigmentation is occasionally seen, and often is the result of spontaneous remission of large hemangiomas.

Considering the few side effects and complications, laser therapy is a valuable tool in the treatment of hemangiomas with rapid uncontrolled growth or affections in functional areas. The main complications of laser therapy include hyperpigmentation, scarring, and atrophy. Surgical correction is often needed for skin scar or residual lesions.

DRUG THERAPY

Systematic or local drug therapy is considered in patients with multiple hemangiomas, rapidly growing hemangiomas, life-threatening hemangiomas or hemangiomas involving vital organs. Laser therapy can be applied during corticosteroids treatment. Several drugs have been successfully used to treat symptomatic hemangiomas to promote stabilization or regression with various responses. The use of corticosteroids to treat hemangiomas of infancy has been practiced for over 40 years since the first report by Zarem and Edgerton12 in 1967. It has become the first-line treatment for large and potentially disfiguring hemangiomas as well as for patients with congestive heart failure, consumptive coagulopathies, and thrombocytopenia. Corticosteroid should be administered during the proliferative phase because they have a negligible effect on involuting otherwise stable lesions. The oral route generally is preferred over intralesional therapy; however, the location, size, patient age, and physician experience factor into the decision-making process.

The prescribed dosage of prednisone or prednisolone in China is 3 to 5 mg/kg every other day rather than per day; given as a single morning dose for 8 weeks. The dose is then gradually tapered to 1.5 to 2.5 mg/kg every other day at the 9th week, 10 mg every other day at the 10th week, 5 mg every other day at the 11th week and discontinued at the 12th week. A second or third course of treatment may be initiated at intervals of 4 to 6 weeks when necessary. Wide variation in response rates exists; from less than 40% to greater than 90%, 84% on average,13 depending on dose, duration of treatment and age at which corticosteroid therapy is initiated. The dose-response relationship was confirmed with a better response with a larger dose, but there was no significant difference in duration of treatment. In addition, corticosteroid therapy should be administrated within 1 year of age, the larger the patient's age at the start of the treatment, the poorer the treatment result.

Corticosteroids are generally well tolerated for the treatment of hemangiomas with no long-term side effects, some transient side effects such as “catch-up” growth, behavior changes (depressed mood, euphoria, insomnia, restlessness, irritability) or cushingoid appearance may occur, but they disappear with stopping of the drug. Corticosteroid therapy may be repeated in patients with rebound growth of the hemangioma without drug resistance.

Intralesional injection of corticosteroids or Bleomycin A5 (Pingyangmycin in China) is effective at slowing the growth and decreasing the size of proliferating hemangiomas. This treatment modality is adaptable to patients with poor response to or with contraindication of oral corticosteroids or laser therapy due to various reasons. The overall response rate of local administration is 94.5%. Locally administered corticosteroids have a similar response rate to systemic administration, but with fewer adverse effects. It has typically been used for periorbital and localized facial lesions. Kushner14 advocates use of a mixture of 40 mg of triamcinolone acetonide (1 ml) and 6 mg of betamethasone acetate (1 ml) that are injected directly into the tumor with a small diameter needle. The injections are repeated at intervals of 6 to 8 weeks for a total of 3 to 5 injections.

Intratumoral injection of Pingyangmycin to treat hemangiomas was first reported by Zheng et al15 in 1991, with progressively more authors adopted this treatment modality in management of head and neck hemangiomas and vascular malformations since then.16 This treatment modality has been proven to be effective, easily performed and safe. Compared with the conventionally used 5% sodium morrhuate; swelling, pain and tissue reactions are mild and necrosis of skin or mucosa seldom occurs post-injection. Therefore, it is especially applicable for treatment of hemangiomas located in the floor of mouth, tongue and submandibular region because swelling after injection in these areas is minimal to prevent compression in the respiratory tract.

Based on our clinical experience complete resolution of small and moderate-sized hemangiomas (less than 4 cm in diameter) in the head and neck can be achieved with intralesional Pingyangmycin injection treatment alone. For larger and deeper hemangiomas, other sclerosing agents, such as 5% sodium morrhuate and absolute ethyl alcohol, are considered allowing for limited need of secondary surgical or adjunctive procedures.

Initially used as an antiviral agent in HIV patients, interferon-α-2a was found to induce regression of Kaposi sarcoma. This led to its use in treating life-threatening proliferating hemangiomas, that have failed to respond to systemic corticosteroids and Kasabach-Merritt syndrome.17 The exact mechanism of action of interferon-α-2a on hemangiomas is unclear. Reported potential mechanisms include inhibiting endothelial cell migration and proliferation and specific growth factors such as endothelial growth factor, fibroblast growth factor, etc. It is usually used at a dosage of 3 million U/m2 given subcutaneously per day for 7 to 10 months. The response rate is varied between 80% and 90%. Unlike steroids, it does not require that administration occur during the proliferation phase to be effective. The onset of action is slower than that of corticosteroids, usually requiring several weeks. Treatment with interferon-α has more side effects than with corticosteroids, including flu-like symptoms, fatigue, lethargy, anorexia, weight loss, proteinuria, and elevation of liver transaminases. If the desired effect is not observed after 1 month, interferon-α should be discontinued.

Recently, the use of imiquimod, a topical immune-modulator, was shown to be efficacious in the treatment of uncomplicated hemangiomas.18,19 Imiquimod is US Food and Drug Administration-approved for the treatment of genital warts and basal cell carcinoma with excellent results and low recurrence. It stimulates innate and acquired immunity through a variety of mechanisms, including the activation of toll-like receptor-7 and the production of a variety of cytokines, including interferon-α and IL-12, through which it may exert antiangiogenic effects.

Only a few case reports are currently available on the use of 5% imiquimod cream for the treatment of infantile hemangiomas. Our experience with 9 cases indicates that this treatment is especially useful for selected small and moderate-sized hemangiomas involving the non-conspicuous regions such as the scalp, nape and the trunk. It is advantageous as it is easy to use for the parents at home, has minimal systemic side effects, acceptable tolerance and can be used simultaneously with oral corticosteroids in patients with multiple hemangiomas. It is applied in small amount topically thrice weekly, usually Monday, Wednesday, and Friday, to affected area for 3 to 5 months, until the lesions resolved completely. Further controlled trials are indicated in order to validate usefulness and safety of imiquimod in the treatment of hemangiomas of infancy, both complicated and uncomplicated.

Several different chemotherapeutic agents have also been used for the treatment of hemangiomas, including cyclophosphamide and vincristine. The exact role of chemotherapy in treating hemangiomas remains unclear at this time and should be reserved only for patients with diffuse uncontrolled hemangiomas using conventional methods.

SURGICAL THERAPY

Surgical excision of hemangiomas is no longer the treatment of choice nowadays, but there are several clear indications for surgical therapy of hemangiomas. Early surgical therapy may be necessary for eyelid or periorbital hemangiomas that may compromise the visual axis, leading to amblyopia, and for large lesions obstructing the larynx, nasal airway, or the ear canal. Surgery may also be considered early for large deforming lesions of the nose, ears, or lips, because hemangiomas on the ears and the tip of the nose (“Cyrano nose”) tend to heal poorly as a result of damage to underlying cartilage, and cosmetic outcome may be improved by surgical excision. Excision is also beneficial for ulcerated or bleeding hemangiomas that have not responded to more conservative treatment. If the lesion is too large and primary closure is impossible, laser therapy may be performed first followed by surgical correction. Late surgical therapy is generally indicated in those hemangiomas that involute with residual scarring, cutaneous redundancy, areas of alopecia on the scalp, or atrophy before school ages, to minimize the psychosocial distress from the presence of hemangiomas for both patient and family.

Nd:YAG laser is usually used as the initial treatment modality for extensive hemangiomas with good and excellent results in most patients, but still 10% to 20% of patients require surgical excision of the residual lesion or sequelae. Laser therapy does not compete in the treatment of infantile hemangiomas, but is complementary with other measures. The interval between laser therapy and surgery should not be too short, because 1 year after laser therapy, the lesion will continue to regress. The following principles are proposed: at 1 year, laser and/or drug therapy; at 2 to 4 years, close observation; at 5 to 6 years, surgical treatment.

In summary, the treatment of hemangiomas should be individualized; factors affecting decision to treat include size, location, depth, growing stage, and trend of the lesion and many others, such as the age of patient, presence, or likelihood of complications, availability of treatment modality, expertise of treating physician and parental preference. Extensive or multiple hemangiomas usually require reasonable combined treatment. A successful regime should be widely adaptable to various types and sizes of hemangiomas, unfortunately, none of the currently available treatment modalities are refractory to standard therapy.

The following suggestions should be taken into account in management of hemangiomas: (1) Drug therapy and laser therapy for proliferating lesions, close observation for stable and involuting lesions; (2) Pulsed dye laser for lesions less than 2 mm in depth and larger than 1.5 cm in size, Nd:YAG laser for lesions in the face with a depth more than 2 mm, drug therapy for multiple lesions; (3) Laser therapy and secondary surgical correction for lesions in the face, surgery and laser therapy for lesions in the scalp and eyelids; (4) Urgent treatment for children less than 6 months, but selective treatment for children more than 6 months; (5) Systematic drug therapy for life-threatening lesions or lesions involving vital organs.

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Keywords:

hemangioma; head and neck; treatment

© 2008 Chinese Medical Association